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1.  Inflammation and cancer-related fatigue: Mechanisms, contributing factors, and treatment implications 
Brain, behavior, and immunity  2012;30(0):S48-S57.
Fatigue is one of the most common and distressing side effects of cancer and its treatment, and may persist for years after treatment completion in otherwise healthy survivors. Guided by basic research on neuro-immune interactions, a growing body of research has examined the hypothesis that cancer-related fatigue is driven by activation of the pro-inflammatory cytokine network. In this review, we examine the current state of the evidence linking inflammation and cancer-related fatigue, drawing from recent human research and from experimental animal models probing effects of cancer and cancer treatment on inflammation and fatigue. In addition, we consider two key questions that are currently driving research in this area: what are the neural mechanisms of fatigue, and what are the biological and psychological factors that influence the onset and/or persistence of inflammation and fatigue in cancer patients and survivors? Identification of the mechanisms driving cancer-related fatigue and associated risk factors will facilitate the development of targeted interventions for vulnerable patients.
doi:10.1016/j.bbi.2012.06.011
PMCID: PMC3978020  PMID: 22776268
2.  The perioperative period and promotion of cancer metastasis: New outlooks on mediating mechanisms and immune involvement 
Brain, behavior, and immunity  2012;30(Suppl):S32-S40.
Surgery for the removal of a primary tumor presents an opportunity to eradicate cancer or arrest its progression, but is also believed to promote the outbreak of pre-existing micrometastases and the initiation of new metastases. These deleterious effects of surgery are mediated through various mechanisms, including psychological and physiological neuroendocrine and paracrine stress responses elicited by surgery. In this review we (i) describe the many risk factors that arise during the perioperative period, acting synergistically to make this short timeframe critical for determining long-term cancer recurrence, (ii) present newly identified potent immunocyte populations that can destroy autologous tumor cells that were traditionally considered immune-resistant, thus invigorating the notion of immune-surveillance against cancer metastasis, (iii) describe in vivo evidence in cancer patients that support a role for anti-cancer immunity, (iv) indicate neuroendocrine and paracrine mediating mechanisms of stress- and surgery-induced promotion of cancer progression, focusing on the prominent role of catecholamines and prostaglandins through their impact on anti-cancer immunity, and through direct effects on the malignant tissue and its surrounding, (v) discuss the impact of different anesthetic approaches and other intra-operative procedures on immunity and cancer progression, and (vi) suggest prophylactic measures against the immunosuppressive and cancer promoting effects of surgery.
doi:10.1016/j.bbi.2012.03.006
PMCID: PMC3423506  PMID: 22504092
Perioperative; metastasis; immunity; stress; surgery; cancer; catecholamines; prostaglanids; glucocorticoids; anesthesia
3.  Early Impact of Social Isolation and Breast Tumor Progression in Mice 
Brain, behavior, and immunity  2012;30(Suppl):S135-S141.
Evidence from cancer patients and animal models of cancer indicates that exposure to psychosocial stress can promote tumor growth and metastasis, but the pathways underlying stress-induced cancer pathogenesis are not fully understood. Social isolation has been shown to promote tumor progression. We examined the impact of social isolation on breast cancer pathogenesis in adult female severe combined immunodeficiency (SCID) mice using the human breast cancer cell line, MDA-MB-231, a high ß-adrenergic receptor (AR) expressing line. When group-adapted mice were transferred into single housing (social isolation) one week prior to MB-231 tumor cell injection into a mammary fat pad (orthotopic), no alterations in tumor growth or metastasis were detected compared to group-housed mice. When social isolation was delayed until tumors were palpable, tumor growth was transiently increased in singly-housed mice. To determine if sympathetic nervous system activation was associated with increased tumor growth, spleen and tumor norepinephrine (NE) was measured after social isolation, in conjunction with tumor-promoting macrophage populations. Three days after transfer to single housing, spleen weight was transiently increased in tumor-bearing and non-tumor-bearing mice in conjunction with reduced splenic NE concentration and elevated CD11b+Gr-1+ macrophages. At day 10 after social isolation, no changes in spleen CD11b+ populations or NE were detected in singly-housed mice. In the tumors, social isolation increased CD11b+Gr-1+, CD11b+Gr-1-, and F4/80+ macrophage populations, with no change in tumor NE. The results indicate that a psychological stressor, social isolation, elicits dynamic but transient effects on macrophage populations that may facilitate tumor growth. The transiency of the changes in peripheral NE suggest that homeostatic mechanisms may mitigate the impact of social isolation over time. Studies are underway to define the neuroendocrine mechanisms underlying the tumor-promoting effects of social isolation, and to determine the contributions of increased tumor macrophages to tumor pathogenesis.
doi:10.1016/j.bbi.2012.05.003
PMCID: PMC3431437  PMID: 22610067
Social isolation; psychosocial stressor; breast cancer; norepinephrine; macrophages; SCID mice
4.  Sleep Disturbance, Inflammation and Depression Risk in Cancer Survivors 
Brain, behavior, and immunity  2012;30(Suppl):S58-S67.
Over two-thirds of the 11.4 million cancer survivors in the United States can expect long-term survival, with many others living with cancer as a chronic disease controlled by ongoing therapy. However, behavioral co-morbidities often arise during treatment and persist long-term to complicate survival and reduce quality of life. In this review, the inter-relationships between cancer, depression, and sleep disturbance are described, with a focus on the role of sleep disturbance as a risk factor for depression. Increasing evidence also links alterations in inflammatory biology dynamics to these long-term effects of cancer diagnosis and treatment, and the hypothesis that sleep disturbance drives inflammation, which together contribute to depression, is discussed. Better understanding of the associations between inflammation and behavioral co-morbidities has the potential to refine prediction of risk and development of strategies for the prevention and treatment of sleep disturbance and depression in cancer survivors.
doi:10.1016/j.bbi.2012.05.002
PMCID: PMC3435451  PMID: 22634367
5.  PSYCHOSOCIAL INTERVENTION EFFECTS ON ADAPTATION, DISEASE COURSE AND BIOBEHAVIORAL PROCESSES IN CANCER 
Brain, behavior, and immunity  2012;30(Suppl):S88-S98.
A diagnosis of cancer and subsequent treatments place demands on psychological adaptation. Behavioral research suggests the importance of cognitive, behavioral, and social factors in facilitating adaptation during active treatment and throughout cancer survivorship, which forms the rationale for the use of many psychosocial interventions in cancer patients. This cancer experience may also affect physiological adaptation systems (e.g., neuroendocrine) in parallel with psychological adaptation changes (negative affect). Changes in adaptation may alter tumor growth-promoting processes (increased angiogenesis, migration and invasion, and inflammation) and tumor defense processes (decreased cellular immunity) relevant for cancer progression and the quality of life of cancer patients. Some evidence suggests that psychosocial intervention can improve psychological and physiological adaptation indicators in cancer patients. However, less is known about whether these interventions can influence tumor activity and tumor growth-promoting processes and whether changes in these processes could explain the psychosocial intervention effects on recurrence and survival documented to date. Documenting that psychosocial interventions can modulate molecular activities (e.g., transcriptional indicators of cell signaling) that govern tumor promoting and tumor defense processes on the one hand, and clinical disease course on the other is a key challenge for biobehavioral oncology research. This mini-review will summarize current knowledge on psychological and physiological adaptation processes affected throughout the stress of the cancer experience, and the effects of psychosocial interventions on psychological adaptation, cancer disease progression, and changes in stress-related biobehavioral processes that may mediate intervention effects on clinical cancer outcomes. Very recent intervention work in breast cancer will be used to illuminate emerging trends in molecular probes of interest in the hope of highlighting future paths that could move the field of biobehavioral oncology intervention research forward.
doi:10.1016/j.bbi.2012.05.009
PMCID: PMC3444659  PMID: 22627072
6.  Neuroendocrine influences on cancer progression 
Brain, behavior, and immunity  2012;30(Suppl):S19-S25.
During the past decade, new studies have continued to shed light on the role of neuroendocrine regulation of downstream physiological and biological pathways relevant to cancer growth and progression. More specifically, our knowledge of the effects of the sympathetic nervous system (SNS) on cancer biology has been greatly expanded by new data demonstrating how the cellular immune response, inflammatory processes, tumor-associated angiogenesis, and tumor cell invasion and survival converge to promote tumor growth. This review will summarize these studies, while synthesizing clinical, cellular and molecular research that has continued to unearth the biological events mediating the interplay between SNS-related processes and cancer progression.
doi:10.1016/j.bbi.2012.06.005
PMCID: PMC3467346  PMID: 22728325
behavioral stress; adrenergic receptors; metastasis; catecholamines; cancer
7.  Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer 
Brain, behavior, and immunity  2012;30(Suppl):S149-S162.
Women respond differentially to the stress-associated with breast cancer diagnosis and treatment, with some women experiencing more intense and/or sustained behavioral symptoms and immune dysregulation than others. Childhood adversity has been identified to produce long-term dysregulation of stress response systems, increasing reactivity to stressors encountered during adulthood. This study determined whether childhood adversity increased vulnerability for more intense and sustained behavioral symptoms (fatigue, perceived stress, and depressive symptoms), poorer quality of life, and greater immune dysregulation in women (N=40) with breast cancer. Evaluation was after breast surgery and through early survivorship. Hierarchical linear modeling was used to examine intra-individual and inter-individual differences with respect to initial status and to the pattern of change (i.e. trajectory) of outcomes. At initial assessment, women exposed to childhood emotional neglect/abuse had greater perceived stress, fatigue, depressive symptoms and poorer quality of life, as well as lower natural killer cell activity (NKCA). Although these outcomes improved over time, women with greater childhood emotional neglect/abuse exhibited worse outcomes through early survivorship. No effect was observed on the trajectory for these outcomes. In contrast, childhood physical neglect predicted sustained trajectories of greater perceived stress, worse quality of life, and elevated plasma IL-6; with no effect observed at initial assessment. Thus, childhood adversity leaves an enduring imprint, increasing vulnerability for behavioral symptoms, poor quality of life, and elevations in IL-6 in women with breast cancer. Further, childhood adversity predisposes to lower NKCA at a critical time when this immune-effector mechanism is most effective at halting nascent tumor seeding.
doi:10.1016/j.bbi.2012.05.014
PMCID: PMC3492527  PMID: 22659062
Childhood Adversity; Childhood Emotional Neglect/Abuse; Childhood Physical Neglect/Abuse; Breast Cancer; Perceived Stress; Depression; Quality of Life; Fatigue; Natural Killer Cell Activity; IL-6
8.  Biobehavioral Influences on Recovery Following Hematopoietic Stem Cell Transplantation 
Brain, behavior, and immunity  2012;30(Suppl):S68-S74.
Hematopoietic stem cell transplantation (HSCT) is a rigorous therapy that carries significant risk of morbidity and mortality to individuals with hematologic malignancies undergoing this treatment. While relationships between psychosocial factors, immune function, and clinical outcomes have been documented in other cancer populations, similar studies of cancer patients undergoing HSCT have not yet been conducted. The clinical significance of these relationships may be particularly salient in this population given the critical role of a timely immune recovery and optimal immune regulation in preventing infections, mitigating risk for graft-versus-host disease, and eliminating malignant cells, thereby reducing morbidity and mortality. Evidence for the potential role of biobehavioral processes following HSCT is reviewed, mechanisms by which psychosocial factors may influence immune processes relevant to post-transplant outcomes are discussed, and a framework to ground future psychoneuroimmunology (PNI) research in this area is provided. The review suggests that the recovery period following HSCT may provide a “window of opportunity” during which interventions targeting stress-related behavioral factors can influence the survival, health, and well-being of HSCT recipients.
doi:10.1016/j.bbi.2012.07.005
PMCID: PMC3493826  PMID: 22820408
9.  Does tumor necrosis factor-alpha (TNF-α) play a role in post-chemotherapy cerebral dysfunction? 
Brain, behavior, and immunity  2012;30(Suppl):S99-S108.
Post-chemotherapy treated cancer patients frequently report cognitive difficulties. The biology of this phenomenon is poorly understood, with uncertainty about possible direct toxic effects on the brain, secondary effects from systemic inflammation, host factors/genetic predisposition to cognitive complaints, or hormonal changes influencing cognitive function. To elucidate possible mechanisms associated with post-treatment cognitive dysfunction among breast cancer survivors, in 2007 we established a prospective, longitudinal, observational cohort study of early stage breast cancer patients, recruited at the end of initial treatments (primary treatment exposure included surgery, ± radiation, ± chemotherapy), and prior to the initiation of adjuvant endocrine therapy. We assessed cognitive complaints, neuropsychological (NP) test performance, markers of inflammation, and brain imaging at baseline, 6 months and 12 months after enrollment. In this analysis of data from the first 93 patients enrolled in the cohort study, we focus on the relationship of circulating levels of proinflammatory cytokines to cerebral functioning and chemotherapy exposure. Among the proinflammatory cytokines tested (IL-1ra, sTNF-RII, CRP, and IL-6) at baseline, only sTNF-RII was increased among chemotherapy exposed patients, with a significant decline in the year after treatment (p=0.003). Higher baseline sTNF-RII was significantly associated with increased memory complaints. In chemotherapy exposed patients, the longitudinal decline in sTNF-RII was significantly correlated with fewer memory complaints over 12 months (r=-0.34, p=0.04). Higher baseline sTNF-RII was also associated with relatively diminished brain metabolism in the inferior frontal cortex (r=-0.55, p=0.02), as well as relatively increased inferior frontal metabolism after one year, in chemotherapy-exposed subjects. These preliminary findings suggest that post-chemotherapy increases in TNF-α may be playing an important role in the manifestations of cognitive complaints in breast cancer survivors.
doi:10.1016/j.bbi.2012.07.015
PMCID: PMC3522786  PMID: 22884417
breast cancer; cognitive complaints; chemotherapy; proinflammatory cytokines; TNF-α; neuropsychological testing; brain imaging
10.  The Effect of Pre-Transplant Distress on Immune Reconstitution among Adult Autologous Hematopoietic Cell Transplantation Patients 
Brain, behavior, and immunity  2012;30(Suppl):S142-S148.
Myeloablative hematopoietic cell transplantation (HCT) is a common treatment for hematological malignancy. Delayed immune reconstitution following HCT is a major impediment to recovery with patients being most vulnerable during the first month after transplant. HCT is a highly stressful process. Because psychological distress has been associated with down regulation of immune function we examined the effect of pre-transplant distress on white blood cell (WBC) count among 70 adult autologous HCT patients during the first 3 weeks after transplant. The participants were on average 38 years old; 93% Caucasian, non-Hispanic and 55% male. Pre-transplant distress was measured 2–14 days before admission using the Cancer and Treatment Distress (CTXD) scale, and the Symptom Checklist-90-R (SCL-90-R) anxiety and depression subscales. WBC count was measured during initial immune recovery on days 5 through 22 post-transplant. Linear mixed model regression analyses controlling for gender and treatment-related variables revealed a significant effect of the mean pre-transplant SCL Depression-Anxiety score on WBC recovery. We found no significant effect of pre-transplant CTXD on WBC recovery. In general, higher levels of pre-treatment depression and anxiety were associated with slower WBC recovery. Psychological modulation of WBC recovery during HCT suggests a unique mechanism by which psychological distress can exert influence over the immune system. Given that WBC recovery is essential to survival for HCT patients, these data provide a rationale for treating anxiety and depression in HCT patients.
doi:10.1016/j.bbi.2012.07.020
PMCID: PMC3549315  PMID: 22910186
hematopoietic cell transplantation; immune reconstitution; cancer treatment-related distress; depression; anxiety; hematologic malignancy; cancer
11.  Systems Biology of Complex Symptom Profiles: Capturing Interactivity across Behavior, Brain and Immune Regulation 
As our thinking about the basic principles of biology and medicine continue to evolve, the importance of context and regulatory interaction is becoming increasingly obvious. Biochemical and physiological components do not exist in isolation but instead are part of a tightly integrated network of interacting elements that ensure robustness and support the emergence of complex behavior. This integration permeates all levels of biology from gene regulation, to immune cell signaling, to coordinated patterns of neuronal activity and the resulting psychosocial interaction. Systems biology is an emerging branch of science that sits as a translational catalyst at the interface of the life and computational sciences. While there is no universally accepted definition of systems biology, we attempt to provide an overview of some the basic unifying concepts and current efforts in the field as they apply to illnesses where brain and subsequent behavior are a chief component, for example autism, schizophrenia, depression, and others. Methods in this field currently constitute a broad mosaic that stretches across multiple scales of biology and physiological compartments. While this work by no means constitutes an exhaustive list of all these methods, this work highlights the principal sub-disciplines presently driving the field as well as future directions of progress.
doi:10.1016/j.bbi.2012.09.008
PMCID: PMC3554865  PMID: 23022717
systems biology; emergent behavior; complexity; network theory; biological scale; regulatory signaling; multi-stability; context-specific behavior; mathematical immunology
12.  PPARγ activation prevents impairments in spatial memory and neurogenesis following transient illness 
The detrimental effects of illness on cognition are familiar to virtually everyone. Some effects resolve quickly while others may linger after the illness resolves. We found that a transient immune response stimulated by lipopolysaccharide (LPS) compromised hippocampal neurogenesis and impaired hippocampus-dependent spatial memory. The immune event caused a 50% reduction in the number of neurons generated during the illness and the onset of the memory impairment was delayed and coincided with the time when neurons generated during the illness would have become functional within the hippocampus. Broad spectrum non-steroidal anti-inflammatory drugs attenuated these effects but selective Cox-2 inhibition was ineffective while PPARγ activation was surprisingly effective at protecting both neurogenesis and memory from the effects of LPS-produced transient illness. These data may highlight novel mechanisms behind chronic inflammatory and neuroinflammatory episodes that are known to compromise hippocampus-dependent forms of learning and memory.
doi:10.1016/j.bbi.2012.10.017
PMCID: PMC3570721  PMID: 23108061
Adult Neurogenesis; Hippocampus; Water Maze; Spatial Memory; Lipopolysaccharide; Neuroinflammation; NSAID; indomethacin; rosiglitazone; C57Bl/6 mice; Doublecortin; NeuN
13.  Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants 
Brain, behavior, and immunity  2013;29:104-112.
Neonatal inflammation is associated with perinatal brain damage. We evaluated to what extent elevated blood levels of inflammation-related proteins supplement information about the risk of impaired early cognitive function provided by inflammation-related illnesses. From 800 infants born before the 28th week of gestation, we collected blood spots on days 1, 7 and 14, for analysis of 25 inflammation-related proteins, and data about culture-positive bacteremia, necrotizing enterocolitis (Bell stage IIIb), and isolated perforation of the intestine, during the first two weeks, and whether they were ventilated on postnatal day 14. We considered a protein to be persistently or recurrently elevated if its concentration was in the top quartile (for gestational age and day blood was collected) on two separate days one week apart. We assessed the children at 2 years of age with the Bayley Mental Development Index (MDI). The combinations of NEC and ventilation on day 14, and of bacteremia and ventilation on day 14 consistently provided information about elevated risk of MDI <55, regardless of whether or not a variable for an elevated protein concentration was included in the model. A variable for a persistently or recurrently elevated concentration of each of the following proteins provided additional information about an increased risk of MDI <55: CRP, SAA, IL-6, TNF-alpha, IL-8, MIP-1beta, ICAM-1, E-SEL, and IGFBP-1. We conclude that elevated blood concentrations of inflammation-related proteins provide information about the risk of impaired cognitive function at age 2 years that supplements information provided by inflammation-associated illnesses.
doi:10.1016/j.bbi.2012.12.012
PMCID: PMC3582030  PMID: 23295265
cognitive impairment; necrotizing enterocolitis; extreme prematurity; systemic inflammatory response; neonatal chronic lung disease; neonatal sepsis
14.  Higher susceptibility to experimental autoimmune encephalomyelitis in Muc1-deficient mice is associated with increased Th1/Th17 responses 
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system in which dendritic cells (DC) play an important role in the development of inflammatory responses. Recently it has been shown that Muc1, a membrane tethered glycoprotein, has an ability to suppress inflammatory responses in cultured DC. The objective of this study was to investigate the possible involvement of Muc1 in the development of MS using experimental encephalomyelitis (EAE) in mice, a widely used animal model of MS. Our results showed that: (1) Muc1−/− mice developed greater EAE severity compared with wild type (wt) mice, which correlated with increased numbers of Th1 and Th17 cells infiltrating into the CNS; (2) Upon stimulation, splenic DC from Muc1−/− mice produced greater amounts of IL-1β, IL-6, and IL-12 but less amounts of IL-10 compared with those from wt mice; and (3) The ability of splenic DC to differentiate antigen-specific CD4+ T cells into Th1 and Th17 cells was greater in Muc1−/− mice compared with wt mice. We conclude that Muc1 plays an anti-inflammatory role in EAE. This is the first report demonstrating the possible involvement of Muc1 in the development of MS and might provide a potential target for immunotherapy.
doi:10.1016/j.bbi.2012.12.004
PMCID: PMC3587144  PMID: 23261777
Multiple sclerosis; Experimental autoimmune encephalomyelitis (EAE); Muc1 mucin; Th1/Th17 cells; Dendritic cells; anti-inflammatory
15.  Nervous system regulation of the cancer genome 
Brain, behavior, and immunity  2012;30(Suppl):S10-S18.
Genomics-based analyses have provided deep insight into the basic biology of cancer and are now clarifying the molecular pathways by which psychological and social factors can regulate tumor cell gene expression and genome evolution. This review summarizes basic and clinical research on neural and endocrine regulation of the cancer genome and its interactions with the surrounding tumor microenvironment, including the specific types of genes subject to neural and endocrine regulation, the signal transduction pathways that mediate such effects, and therapeutic approaches that might be deployed to mitigate their impact. Beta-adrenergic signaling from the sympathetic nervous system has been found to up-regulated a diverse array of genes that contribute to tumor progression and metastasis, whereas glucocorticoid-regulated genes can inhibit DNA repair and promote cancer cell survival and resistance to chemotherapy. Relationships between socio-environmental risk factors, neural and endocrine signaling to the tumor microenvironment, and transcriptional responses by cancer cells and surrounding stromal cells are providing new mechanistic insights into the social epidemiology of cancer, new therapeutic approaches for protecting the health of cancer patients, and new molecular biomarkers for assessing the impact of behavioral and pharmacologic interventions.
doi:10.1016/j.bbi.2012.11.008
PMCID: PMC3600385  PMID: 23207104
16.  Effects of Voluntary Wheel Running on LPS-induced Sickness Behavior in Aged Mice 
Brain, behavior, and immunity  2012;29:113-123.
Peripheral stimulation of the innate immune system with LPS causes exaggerated neuroinflammation and prolonged sickness behavior in aged mice. Regular moderate intensity exercise has been shown to exert anti-inflammatory effects that may protect against inappropriate neuroinflammation and sickness in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced sickness behavior and proinflammatory cytokine gene expression in ~22-month-old C57BL/6J mice. Mice were housed with a running wheel (VWR), locked-wheel (Locked), or no wheel (Standard) for 10 weeks, after which they were intraperitoneally injected with LPS across a range of doses (0.02, 0.08, 0.16, 0.33 mg/kg). VWR mice ran on average 3.5 km/day and lost significantly more body weight and body fat, and increased their forced exercise tolerance compared to Locked and Shoebox mice. VWR had no effect on LPS-induced anorexia, adipsia, weight-loss, or reductions in locomotor activity at any LPS dose when compared to Locked and Shoebox groups. LPS induced sickness behavior in a dose-dependent fashion (0.33>0.02 mg/kg). Twenty-four hours post-injection (0.33mg/kg LPS or Saline) we found a LPS-induced upregulation of whole brain TNFα, IL-1β, and IL-10 mRNA, and increased IL-1β and IL-6 in the spleen and liver; these effects were not attenuated by VWR. We conclude that VWR does not reduce LPS-induced exaggerated or prolonged sickness behavior in aged animals, or 24h post-injection (0.33mg/kg LPS or Saline) brain and peripheral proinflammatory cytokine gene expression. The necessity of the sickness response is critical for survival and may outweigh the subtle benefits of exercise training in aged animals.
doi:10.1016/j.bbi.2012.12.014
PMCID: PMC3619400  PMID: 23277090
17.  Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: A replication and extension study 
Brain, behavior, and immunity  2012;30(0):S117-S125.
Cognitive changes related to cancer and its treatment have been intensely studied, and neuroimaging has begun to demonstrate brain correlates. In the first prospective longitudinal neuroimaging study of breast cancer (BC) patients we recently reported decreased gray matter density one month after chemotherapy completion, particularly in frontal regions. These findings helped confirm a neural basis for previously reported cognitive symptoms, which most commonly involve executive and memory processes in which the frontal lobes are a critical component of underlying neural circuitry. Here we present data from an independent, larger, more demographically diverse cohort that is more generalizable to the BC population. BC patients treated with (N = 27) and without (N = 28) chemotherapy and matched healthy controls (N = 24) were scanned at baseline (prior to systemic treatment) and one month following chemotherapy completion (or yoked intervals for non-chemotherapy and control groups) and APOE-genotyped. Voxel-based morphometry (VBM) showed decreased frontal gray matter density after chemotherapy, as observed in the prior cohort, which was accompanied by self-reported difficulties in executive functioning. Gray matter and executive symptom changes were not related to APOE ε4 status, though a somewhat greater percentage of BC patients who received chemotherapy were ε4 allele carriers than patients not treated with chemotherapy or healthy controls. These findings provide confirmatory evidence of frontal morphometric changes that may be a pathophysiological basis for cancer and treatment-related cognitive dysfunction. Further research into individual risk factors for such changes will be critical for development of treatment and prevention strategies.
doi:10.1016/j.bbi.2012.05.007
PMCID: PMC3629547  PMID: 22613170
Adjuvant chemotherapy; APOE genotype; Brain; Breast cancer; BRIEF-A; Executive function; Frontal lobes; Magnetic resonance imaging; Neuroimaging; Voxel-based morphometry
18.  Effects and potential mechanisms of exercise training on cancer progression: A translational perspective 
Brain, behavior, and immunity  2012;30(0):S75-S87.
Over the past decade there has been increasing research and clinical interest in the role of exercise therapy/rehabilitation as an adjunct therapy to improve symptom control and management following a cancer diagnosis. More recently, the field of ‘exercise – oncology’ has broadened in scope to investigate whether the benefits extend beyond symptom control to modulate cancer-specific outcomes (i.e., cancer progression and metastasis). Here we review the extant epidemiological evidence examining the association between exercise behavior, functional capacity/exercise capacity, and cancer-specific recurrence and mortality as well as all-cause mortality individuals following a cancer diagnosis. We also evaluate evidence from clinical studies investigating the effects of structured exercise on blood-based biomarkers associated with cancer progression/metastasis as well findings from preclinical investigations examining the effects and molecular mechanisms of exercise in mouse models of cancer. Current gaps in knowledge are also discussed.
doi:10.1016/j.bbi.2012.05.001
PMCID: PMC3638811  PMID: 22610066
Exercise; Physical activity; Mouse models; Cancer; Carcinogenesis; Mechanisms
19.  Cortisol and Inflammatory Processes in Ovarian Cancer Patients Following Primary Treatment: Relationships with Depression, Fatigue, and Disability 
Brain, behavior, and immunity  2012;30(0):S126-S134.
Elevations in the pro-inflammatory cytokine interleukin-6 (IL-6) and alterations in the anti-inflammatory hormone cortisol have been reported in a variety of cancers. IL-6 has prognostic significance in ovarian cancer and cortisol has been associated with fatigue, disability, and vegetative depression in ovarian cancer patients prior to surgery. Ovarian cancer patients undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at six months, and at one year. Patients included in this study had completed chemotherapy and had no evidence of disease recurrence. At six months, patients showed significant reductions in nocturnal cortisol secretion, plasma IL-6, and a more normalized diurnal cortisol rhythm, changes that were maintained at one year. The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability. These findings suggest that primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by one year appear to maintain more normalized levels of cortisol and IL-6. Improvement in fatigue and vegetative depression is associated with the normalization of IL-6 and cortisol, a pattern which may be relevant for improvements in overall quality of life for ovarian cancer patients.
doi:10.1016/j.bbi.2012.07.022
PMCID: PMC3697797  PMID: 22884960
ovarian cancer; fatigue; depression; disability; cortisol; IL-6; inflammation
20.  Psychoneuroimmunology and cancer: A decade of discovery, paradigm shifts, and methodological innovations 
Brain, behavior, and immunity  2013;30(0):S1-S9.
This article introduces the supplemental issue of “Cancer, Brain, Behavior, and Immunity” and outlines important discoveries, paradigm shifts, and methodological innovations that have emerged in the past decade to advance mechanistic and translational understanding of biobehavioral influences on tumor biology, cancer treatment-related sequelae, and cancer outcomes. We offer a heuristic framework for research on biobehavioral pathways in cancer. The shifting survivorship landscape is highlighted and we propose that the changing demographics suggest prudent adoption of a life course perspective of cancer and cancer survivorship. We note opportunities for psychoneuroimmunology (PNI) research to ameliorate the long-term, unintended consequences of aggressive curative intent and call attention to the critical role of reciprocal translational pathways between animal and human studies. Lastly, we briefly summarize the articles included in this compilation and offer our perspectives on future research directions. HighlightsThis article introduces the National Cancer Institute sponsored special issue Cancer, Brain, Behavior, and Immunity and highlights the last decade of PNI-cancer research.
doi:10.1016/j.bbi.2013.01.003
PMCID: PMC3907949  PMID: 23333846
biobehavioral; psycho-oncology; tumor biology; cancer treatment; cancer outcomes
21.  Failure of thyroid hormone treatment to prevent inflammation-induced white matter injury in the immature brain 
Brain, Behavior, and Immunity  2014;37(100):95-102.
Highlight
•Thyroid hormone treatment did not recover deficits in oligodendrocyte maturation and myelination in a mouse model of preterm inflammation-induced white matter damage.
Preterm birth is very strongly associated with maternal/foetal inflammation and leads to permanent neurological deficits. These deficits correlate with the severity of white matter injury, including maturational arrest of oligodendrocytes and hypomyelination. Preterm birth and exposure to inflammation causes hypothyroxinemia. As such, supplementation with thyroxine (T4) seems a good candidate therapy for reducing white matter damage in preterm infants as oligodendrocyte maturation and myelination is regulated by thyroid hormones.
We report on a model of preterm inflammation-induced white matter damage, in which induction of systemic inflammation by exposure from P1 to P5 to interleukin-1β (IL-1β) causes oligodendrocyte maturational arrest and hypomyelination. This model identified transient hypothyroidism and wide-ranging dysfunction in thyroid hormone signalling pathways. To test whether a clinically relevant dose of T4 could reduce inflammation-induced white matter damage we concurrently treated mice exposed to IL-1β from P1 to P5 with T4 (20 μg/kg/day). At P10, we isolated O4-positive pre-oligodendrocytes and gene expression analysis revealed that T4 treatment did not recover the IL-1β-induced blockade of oligodendrocyte maturation. Moreover, at P10 and P30 immunohistochemistry for markers of oligodendrocyte lineage (NG2, PDGFRα and APC) and myelin (MBP) similarly indicated that T4 treatment did not recover IL-1β-induced deficits in the white matter.
In summary, in this model of preterm inflammation-induced white matter injury, a clinical dose of T4 had no therapeutic efficacy. We suggest that additional pre-clinical trials with T4 covering the breadth and scope of causes and outcomes of perinatal brain injury are required before we can correctly evaluate clinical trials data and understand the potential for thyroid hormone as a widely implementable clinical therapy.
doi:10.1016/j.bbi.2013.11.005
PMCID: PMC3969588  PMID: 24240022
Prematurity; Thyroxine; Oligodendrocyte; Myelination; Neuroprotection
22.  Depression, C-reactive protein and length of post-operative hospital stay in coronary artery bypass graft surgery patients 
Brain, Behavior, and Immunity  2014;37(100):115-121.
Highlight
•Elevated depression symptoms prior to CABG were associated with increased odds of extended hospital stays and post-operative CRP responses mediated this association.
This study aimed to explore the role of C-reactive protein (CRP) in mediating the association between greater pre-operative depression symptoms and longer post-operative length of stay in patients undergoing coronary artery bypass graft (CABG) surgery. We used a sample of 145 elective CABG patients and measured depression symptoms using the Beck Depression Inventory (BDI) prior to surgery and collected baseline measures of CRP. Participants were followed up during their in-hospital stay to measure early (1–3 days post-surgery) and persistent (4–8 days post-surgery) CRP responses to surgery. We found that compared with participants with low depression symptoms, those with elevated depression symptoms (BDI > 10) prior to CABG were at increased odds of a hospital stay of greater than one week (OR 3.51, 95% CI 1.415–8.693, p = 0.007) and that greater persistent CRP responses mediated this association. Further work is needed to explore the exact physiological pathways through which depression and CRP interact to affect recovery in CABG patients.
doi:10.1016/j.bbi.2013.11.008
PMCID: PMC3969589  PMID: 24239712
Depression; C-reactive protein; Coronary artery bypass grafting; Recovery
23.  Endomorphin 1 and Endomorphin 2 Suppress in vitro Antibody Formation at Ultra-low Concentrations: Anti-Peptide Antibodies But Not Opioid Antagonists Block the Activity 
Brain, behavior, and immunity  2008;22(6):824-832.
Endomorphin 1 (EM-1) and endomorphin 2 (EM-2) were tested for their capacity to alter immune function. Addition of either of these peptides to murine spleen cells in vitro inhibited antibody formation to sheep red blood cells in a bi-phasic dose dependent manner. Maximal inhibition was achieved at doses in the range of 10−13 to 10−15 M. Neither naloxone (general opioid receptor antagonist) nor CTAP (selective mu opioid receptor antagonist) blocked the immunosuppressive effect. To show that there was specificity to the immunosuppressive activity of the peptides, affinity purified rabbit antibodies were raised against each of the synthetic EM peptides haptenized to KLH and tested for capacity to inhibit immunosuppression. Antibody responses were monitored by a standard solid phase antibody capture ELISA assay, and antibodies were purified by immunochromatography using the synthetic peptides coupled to a Sepharose 6B resin. Verification of the specificity of affinity-purified antisera was performed by immunodot-blot and solid-phase RIA assays. The antisera specific for both EM-1 and EM-2 neutralized the immunosuppressive effects of their respective peptides in a dose-related manner. Control normal rabbit IgG had no blocking activity on either EM-1 or EM-2. These studies show that the endomorphins are immunomodulatory at ultra-low concentrations, but the data do not support a mechanism involving the mu opioid receptor.
doi:10.1016/j.bbi.2008.02.004
PMCID: PMC3926125  PMID: 18374539
24.  Neurobiological markers of exercise-related brain plasticity in older adults 
The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) - putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age = 66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.
doi:10.1016/j.bbi.2012.10.021
PMCID: PMC3544982  PMID: 23123199
exercise; aging; functional connectivity; fMRI; default mode network; aerobic fitness; growth factors
25.  Socioeconomic Factors and Leukocyte Telomere Length In A Multi-Ethnic Sample: Findings From The Multi-Ethnic Study of Atherosclerosis (MESA) 
Brain, behavior, and immunity  2012;28:108-114.
Previous findings have linked lower socioeconomic status (SES) with elevated morbidity and mortality. Leukocyte telomere length (LTL), which also has been associated with age-related disease morbidity and mortality, is a marker of aging at the cellular level, making it a valuable early biomarker of risk and an indicator of biological age. It is hypothesized that SES will be associated with LTL, indicating that SES influences disease risk by accelerating biological aging. In the present sample we test for associations of childhood SES and adult SES (i.e. education, income, home ownership) with LTL, and examine whether these associations vary by racial/ethnic group. Analyses on 963 subjects (18.7% White, 53% Hispanics, and 28.5% African American) from the Stress ancillary study of the Multi-Ethnic Study of Atherosclerosis revealed a significant difference in LTL between home owners and renters in Hispanic and White participants (p < .05), but not amongst African Americans (p = .98). There were no linear associations of adult education or family income with LTL, however, there was an inverse association between father’s education and LTL (p = .03). These findings suggest that for Whites and Hispanics renting vs. owning a home is associated with an older biological age; however we did not replicate previous findings linking education with LTL.
doi:10.1016/j.bbi.2012.10.024
PMCID: PMC3544984  PMID: 23142704
Telomere length; childhood SES; socioeconomic status; home ownership; wealth; parental education; cellular aging; biological aging; ethnicity

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